Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist and Associate Professor of Medicine in Chicago. I'm so excited to have here with me today, a good friend and colleague, Dr. Rana McKay, who is an Associate Professor of Medicine and Urology at the University of California San Diego site at the Morris Cancer Center. So excited to have him here today, Dr. McKay, to talk about your RadiCaL study for patients with renal cell carcinoma. Can you tell us a little bit about the study schema and why you put this together?

Rana McKay: Sure. First I can start off by, we know that about 30% of patients with renal cell carcinoma have bone metastases and multiple studies have demonstrated that these patients actually have an inferior outcome compared to patients that don't have bone metastases. They have decrements in their quality of life and morbidity that they suffer related to the bone metastases and actually, it also compromises their mortality when we look at patients that have bone mets versus those that don't have bone metastases. Radium-223 is a liquid radiopharmaceutical that's already FDA approved for the treatment of men with metastatic castration-resistant prostate cancer and has shown improvements in overall survival and actually, improvements in decreased skeletal-related events, symptomatic skeletal-related events, and improvements in quality of life based on results of a large Phase III trial called the ALSYMPCA trial. And this is actually the only radiopharmaceutical that has demonstrated improvements in overall survival for any solid tumor.

And so what we're doing in the context of the RadiCaL trial, which is really built on a pilot study that we conducted with doctors Tony Choueiri at the Dana Farber, where we tested radium-223 with combination VEGF therapy in patients with advanced renal cell carcinoma and demonstrated safety and also demonstrated that markers of bone turnover, both formation, and resorption, declined with the utilization of radium. And that really provided the rationale for us to move forward with the RadiCaL trial.

The RadiCaL trial is looking at testing the combination of cabozantinib with or without radium-223 in men and women with renal cell carcinoma that have bone metastases. They need to have two or more bone metastases present and at least one bone metastasis that hasn't been radiated. We're enrolling patients with any histology, both clear cell and non-clear cell onto the trial. There is a cap of 20% for the non-clear cell patients, reflecting the general population of what we see with regards to histology. Patients need to have symptomatic disease or a prior skeletal-related event and symptomatic disease can be the use of any sort of analgesics for the trial, whether that be Tylenol® or ibuprofen or even narcotics, whatever it may be to control symptoms that are related to the bone metastases or if they had a prior skeletal-related event, that would be part of the eligibility criteria.

We are allowing patients who have bone-only disease to enroll. They don't necessarily need to have measurable disease to enroll in the trial. And patients will be randomized one to one to receive the combination of cabozantinib plus radium versus cabozantinib alone. And we know that cabozantinib has demonstrated efficacy in RCC based on a large Phase III trial called the METEOR trial and also the CABOSUN trial, which demonstrated efficacy in the frontline space for patients with advanced renal cell carcinoma.

The primary endpoint of the trial is a reduction in symptomatic skeletal-related events and secondary endpoints include progression-free survival, overall survival, safety tolerability, quality of life. We'll certainly be embedding correlative analyses with both blood and tissue-based work that will be done.

Alicia Morgans: That's fantastic. And I love all the correlatives that you're putting into the trial because as you mentioned, it is really difficult to understand how things are working when we're really kind of targeting this bone compartment. And we have seen some difficulties in those kinds of studies with prostate cancer, at least with cabozantinib actually. But it's really exciting to me that you're combining this drug, cabozantinib, which we know is efficacious in this patient population and we're really trying to improve their quality of life, reduce the skeletal-related events, but also then seeing if there's a synergy that provides better disease control in this setting. And I think that from a patient perspective, that's really exciting too. If both of those can be improved, that's phenomenal. And of course from a clinician perspective, if we have these really detailed correlative studies that help us understand why that's happening and also understand which patients may benefit most, it's critical and helps us to understand who we can treat and what we can expect. How many sites are you targeting to engage with this trial?

Rana McKay: Yeah, so this is a large trial that's being run through the Alliance Clinical Trials group. It will be run across the US and also Canada. Right now I believe there are 193 sites that have signed up to participate in the trial. We're super excited about that. And certainly, anybody that's involved in the NCTN can participate and get this trial up and running at their site. We are more than happy to work with the sites in getting the study up and going. This is actually one of the first studies that the NCI is running where radium-223 is actually an investigational agent. We are eager to partner with any site that would be interested in helping either the nuclear medicine department or radiation oncology department, whichever department administers standard of care radium because the process is not all that different from utilization just in routine care, but there's some credentialing stuff required and we're more than happy to work with anybody that is interested in getting the study up and going.

Alicia Morgans: And both drugs are actually provided for the patients, right?

Rana McKay: That is correct. Both drugs will be provided through the NCI, both radium-223 and also the cabozantinib. That'll certainly be a saver for the patients and also physicians as well.

Alicia Morgans: Outstanding. If a patient is really keen to engage, how does somebody or a clinician send a patient to participate? Because there are so many patients who are going to be getting potentially standard of care cabozantinib who I think would want to at least consider this as an option. How does that patient, or how does that physician get the patient to where he or she needs to be to enroll?

Rana McKay: Yeah, so there are many sites that are slated to get the study up and enrolling and I would probably recommend going to clinicaltrials.gov and just looking for your nearest site to be activated. And if you are part of the NCTN and want to get the study up and activated at your site, we're more than happy to work with you in doing that. And hopefully, it should be a smooth process given the fact that the study is approved through the central IRB and it's a cooperative group study. A lot of those logistics have sort of already been worked out with cooperative group trials.

Alicia Morgans: That's fantastic. Really going to clinicaltrials.gov and we'll make sure that we have the link in the information. We'll provide any information we can too for sites who might be interested in opening to reach out and partner with the Alliance to get this open. Again, this is standard of care cabozantinib, where we're adding on radium for those patients who have symptomatic bone metastases. And I think that if we have the opportunity to participate in a trial, particularly one that could touch so many patients' lives, it's really an exciting opportunity, especially if it helps all of us patients and docs understand why things are working in and in whom they may work best. If you had to give a final comment to folks, what would that be?

Rana McKay: Honestly, this is a landmark trial because we're taking a radiopharmaceutical that has really not been tested in other disease spaces. There have been some small studies in breast and small studies in multiple myeloma, but we're really trying to change practice with a drug with a very novel mechanism of action that has demonstrated efficacy in another disease context and really trying to apply it in the RCC space. I think if this trial is positive, I do think that there is the potential that it could change the way we practice and think about how we target these patients that have bone metastases.

Alicia Morgans: Well, fantastic. Congratulations, Dr. McKay on getting together. I know it is no easy feat to do certainly the initial trial to look at the safety and the initial early efficacy and then to really launch this Phase II. It is no small feat. Congratulations. We're excited to see where things ultimately end up and we encourage you and your team to enroll and for patients to engage because we really do need to find answers and this is the best way to do it. Thank you so much for your time and all of your efforts.

Rana McKay: Thank you so much, Dr. Morgans.